The overall objective of this work is to further our understanding of the relationship between changes in brain cellular activity, caused by the functional activity of the brain in neurologically normal humans, and changes in blood flow and metabolism. Everyone agrees that the resting brain metabolizes glucose aerobically as its main source of energy. On the basis it was assumed that changes in the activity of the brain would be accompanied by parallel changes in blood glow, glucose utilization and oxygen consumption. It came as a considerable surprise when work with positron emission tomography (PET), supported previously under this program project [Fox, 1986#18][Fox, 1988#19], revealed parallel changes in glucose utilization and blood flow unaccompanied by changes in oxygen consumption. This important observation has not only catalyzed a re- evaluation of these relationships but also provided the physiological rationale for functional mapping of the human brain with magnetic resonance imaging (MRI). Despite the immense interest in functional mapping of the brain, uncertainty surrounds our understanding of these functionally-induced metabolic and circulatory changes. This project addresses two central questions concerning that understanding. First, do the changes in blood flow exceed those of oxygen consumption simply to maintain adequate tissue oxygen. To answer this question we propose to examine blood flow responses as a function of oxygen availability. Second, if glucose is used but only metabolized to lactate, why don't tissue lactate levels adequately reflect the increased glycolysis? To answer this question we propose to determine whether lactate egress from brain is facilitated in areas of increased functional activity. These experiments will provide valuable new information on the relationship of brain functional activity to brain energy metabolism in neurologically normal humans and a sounder scientific basis for functional brain imaging with PET and fMRI.